Faculty Bibliography

Although the intestinal microbiome has been increasingly implicated in autoimmune diseases, much is unknown about its roles in Multiple Sclerosis (MS). Our aim was to compare the microbiome between treatment-naïve MS subjects early in their disease course and controls, and between Caucasian (CA), Hispanic (HA), and African American (AA) MS subjects. From fecal samples, we performed 16S rRNA V4 sequencing and analysis from 45 MS subjects (15 CA, 16 HA, 14 AA) and 44 matched healthy controls, and whole metagenomic shotgun sequencing from 24 MS subjects (all newly diagnosed, treatment-naïve, and steroid-free) and 24 controls. In all three ethnic groups, there was an increased relative abundance of the same single genus, Clostridium, compared to ethnicity-matched controls. Analysis of microbiota networks showed significant changes in the network characteristics between combined MS cohorts and controls, suggesting global differences not restricted to individual taxa. Metagenomic analysis revealed significant enrichment of individual species within Clostridia as well as particular functional pathways in the MS subjects. The increased relative abundance of Clostridia in all three early MS cohorts compared to controls provides candidate taxa for further study as biomarkers or as etiologic agents in MS.

Human anterior and posterior hippocampus (aHC, pHC) differ in connectivity and behavioral correlates. Here we report physiological differences in humans of both sexes. During NREM sleep, the human hippocampus generates sharpwave-ripples (SWR) similar to those which in rodents mark memory replay. We show that while pHC generates SWR, it also generates about as many spindle-ripples (SSR: ripples phase-locked to local spindles). In contrast, SSR are rare in aHC. Like SWR, SSR often co-occur with neocortical theta bursts (TB), downstates (DS), spindles (SS) and upstates (US), which coordinate cortico-hippocampal interactions and facilitate consolidation in rodents. SWR co-occur with these waves in widespread cortical areas, especially fronto-central. These waves typically occur in the sequence TB-DS-SS-US, with SWR usually occurring prior to SS-US. In contrast, SSR occur ∼350 ms later, with a strong preference for co-occurrence with posterior-parietal SS. pHC-SS were strongly phase-locked with parietal-SS, and pHC-SSR were phase-coupled with pHC-SS and parietal-SS. Human SWR (and associated replay events, if any) are separated by ∼5 s on average, whereas ripples on successive SSR peaks are separated by only ∼80 ms. These distinctive physiological properties of pHC-SSR enable an alternative mechanism for hippocampal engagement with neocortex.SIGNIFICANCE STATEMENTRodent hippocampal neurons replay waking events during sharpwave-ripples in NREM sleep, facilitating memory transfer to a permanent cortical store. We show that human anterior hippocampus also produces sharpwave-ripples, but spindle-ripples predominate in posterior. Whereas sharpwave-ripples typically occur as cortex emerges from inactivity, spindle-ripples typically occur at peak cortical activity. Furthermore, posterior hippocampal spindle-ripples are tightly coupled to posterior parietal locations activated by conscious recollection. Finally, multiple spindle-ripples can recur within a second, whereas sharpwave-ripples are separated by about 5s. The human posterior hippocampus is considered homologous to rodent dorsal hippocampus, which is thought to be specialized for consolidation of specific memory details. We speculate that these distinct physiological characteristics of posterior hippocampal spindle-ripples may support a related function in humans.

The positive halochromism of the solvatochromic 4-nitro-4'-(N,N-dimethylamino)-2,2'-bithiophene in acetone and 1-butanol was investigated by molecular dynamics simulations and quantum mechanics calculations. Interactions of the dye with the solvated sodium cation were found to have only a minor effect on the observed halochromism, which was ultimately ascribed to a predominant interaction between iodide anions and the N,N-dimethylamino group of the dye.

Introduction: Dyskinesia is a motor complication of Parkinson's disease (PD) characterized by clinical heterogeneity and complex pathogenesis and associated with long-term levodopa therapy. Recent and controversial views on the management of PD patients have suggested that overall dyskinesia rates, and particularly troublesome dyskinesia, may be declining due to more conservative levodopa dosing regimens, widespread availability and early introduction of deep brain stimulation, and use of continuous drug delivery strategies. Nevertheless, anti-dyskinetic agents continue to be evaluated in clinical trials and recent efforts have focused on non-dopaminergic as well as dopaminergic drugs. Areas covered: In this review, the authors discuss the clinical phenomenology and current understanding of dyskinesia in PD with a focus on up-to-date therapeutic strategies to prevent and manage these drug-related involuntary movements. Expert opinion: The way dyskinesia in PD is currently managed should be changed and attention should be focused towards a more personalized medicine rather than a one-fits-all-approach. The correct identification of dyskinesia types and tailored treatments are crucial for a better management of these involuntary movements together with a holistic approach which considers additional influencing factors. The future for dyskinesia treatment is likely to be found in non-dopaminergic approaches, first set into motion by the introduction of amantadine.

Dynamic interactions between remote but functionally specialized brain regions enable complex information processing. This intercortical communication is disrupted in the neural networks of patients with focal epilepsy, and epileptic activity can exert widespread effects within the brain. Using large-scale human intracranial electroencephalography recordings, we show that interictal epileptiform discharges (IEDs) are significantly coupled with spindles in discrete, individualized brain regions outside of the epileptic network. We found that a substantial proportion of these localized spindles travel across the cortical surface. Brain regions that participate in this IED-driven oscillatory coupling express spindles that have a broader spatial extent and higher tendency to propagate than spindles occurring in uncoupled regions. These altered spatiotemporal oscillatory properties identify areas that are shaped by epileptic activity independent of IED or seizure detection. Our findings suggest that IED-spindle coupling may be an important mechanism of interictal global network dysfunction that could be targeted to prevent disruption of normal neural activity.

OBJECTIVE: Traumatic brain injury (TBI) is the most common cause of death and disability in persons between 15 and 30 years of age. Although various pharmacological agents have been reported to enhance consciousness recovery, few trials have studied these medications in patients with acute TBI. The objective of this study was to determine the effect of modafinil, methylphenidate, amantadine, and zolpidem in improving wakefulness in patients with TBI in an intensive care unit (ICU) setting and to identify any adverse drug reactions. METHODS: Retrospective chart review identified all patients prescribed modafinil, methylphenidate, amantadine, or zolpidem; only patients older than 18 years with TBI in an ICU setting were further analyzed. The electronic medical record was used to retrieve clinical data including patient demographics, mechanism of TBI, drug dosage, treatment duration, Glasgow Coma Scale (GCS) score, length of time to improve GCS score, hospital length of stay, reported adverse drug reactions associated with above medications, and mortality. The primary outcome was the rate of positive response in the clinical neurological exam. Secondary outcomes included change in baseline and final GCS score, time to response, duration of treatment, change in GCS score over time, length of hospital stay, and in-hospital mortality. Descriptive statistics were used to analyze the data. RESULTS: The final analysis included a total of 53 patients. Median ages ranged from 44.0 to 61.5 years; 85% of patients were male. Baseline median GCS score was 8.0 in the amantadine group; 6.5, modafinil; 7.5, methylphenidate; and 7.0, zolpidem. The highest positive response rate was 90% in the amantadine group, followed by modafinil, 77%; methylphenidate, 50%; and zolpidem, 36%. The change in baseline GCS score and median final GCS score for amantadine, modafinil, methylphenidate, and zolpidem was 2.5, 3.0, 1.0, and 0, respectively (P = 0.20). The median time to response in days was 1.5, 1.0, 0.5, and 1.0, respectively. Change in GCS score over time for amantadine, modafinil, methylphenidate, and zolpidem was 0.16, 0.38, 0.12, and 0, respectively. Though rare, the most common adverse events were agitation, hypertension, and posturing. CONCLUSION: It remains to be determined if these medications have a role in reducing ICU and hospital length of stay, length of mechanical ventilation, tracheostomies, and overall medical costs in managing TBI patients. In our study amantadine was associated with the highest overall positive response rate when used as an awakening agent in TBI. Modafinil was associated with the largest change in GCS score over time.

We analyze the role of inhibition in sustaining focal epileptic seizure activity. We review ongoing seizure activity at the mesoscopic scale that can be observed with microelectrode arrays as well as at the macroscale of standard clinical EEG. We provide clinical, experimental, and modeling data to support the hypothesis that paroxysmal depolarization (PD) is a critical component of the ictal machinery. We present dual-patch recordings in cortical cultures showing reduced synaptic transmission associated with presynaptic occurrence of PD, and we find that the PD threshold is cell size related. We further find evidence that optically evoked PD activity in parvalbumin neurons can promote propagation of neuronal excitation in neocortical networks in vitro. Spike sorting results from microelectrode array measurements around ictal wave propagation in human focal seizures demonstrate a strong increase in putative inhibitory firing with an approaching excitatory wave, followed by a sudden reduction of firing at passage. At the macroscopic level, we summarize evidence that this excitatory ictal wave activity is strongly correlated with oscillatory activity across a centimeter-sized cortical network. We summarize Wilson-Cowan-type modeling showing how inhibitory function is crucial for this behavior. Our findings motivated us to develop a network motif of neurons in silico, governed by a reduced version of the Hodgkin-Huxley formalism, to show how feedforward, feedback, PD, and local failure of inhibition contribute to observed dynamics across network scales. The presented multidisciplinary evidence suggests that the PD not only is a cellular marker or epiphenomenon but actively contributes to seizure activity.NEW & NOTEWORTHY We present mechanisms of ongoing focal seizures across meso- and macroscales of microelectrode array and standard clinical recordings, respectively. We find modeling, experimental, and clinical evidence for a dual role of inhibition across these scales: local failure of inhibition allows propagation of a mesoscopic ictal wave, whereas inhibition elsewhere remains intact and sustains macroscopic oscillatory activity. We present evidence for paroxysmal depolarization as a mechanism behind this dual role of inhibition in shaping ictal activity.